An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101
Robert C Doebele, Lara E Davis, Aria Vaishnavi, Anh T Le, Adriana Estrada-Bernal, Stephen Keysar, Antonio Jimeno, Marileila Varella-Garcia, Dara L Aisner, Yali Li, Philip J Stephens, Deborah Morosini, Brian B Tuch, Michele Fernandes, Nisha Nanda, Jennifer A Low, Robert C Doebele, Lara E Davis, Aria Vaishnavi, Anh T Le, Adriana Estrada-Bernal, Stephen Keysar, Antonio Jimeno, Marileila Varella-Garcia, Dara L Aisner, Yali Li, Philip J Stephens, Deborah Morosini, Brian B Tuch, Michele Fernandes, Nisha Nanda, Jennifer A Low
Abstract
Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways. These TRK fusions occur rarely, but in a diverse spectrum of tumor histologies. LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. Preclinical models of LOXO-101 using TRK-fusion-bearing human-derived cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro, and tumor growth in vivo. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an LMNA-NTRK1 gene fusion encoding a functional LMNA-TRKA fusion oncoprotein as determined by an in situ proximity ligation assay. In a phase I study of LOXO-101 (ClinicalTrials.gov no. NCT02122913), this patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers.
Significance: TRK fusions have been deemed putative oncogenic drivers, but their clinical significance remained unclear. A patient with a metastatic soft-tissue sarcoma with an LMNA-NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting TRK fusions.
Conflict of interest statement
Conflicts of Interest
RCD has received consultant fees and is the recipient of a research grant from Loxo Oncology. RCD, ATL, and MVG have received licensing fees from Abbott Molecular for US Patent Application No. 14/423,867.
YL, PJS and DM are employees and stockholders of Foundation Medicine.
BBT, MF, NN, and JAL are employees and stockholders of Loxo Oncology.
©2015 American Association for Cancer Research.
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Source: PubMed